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State Food and Drug Administration issued a document to provide guidance for the control of nitrosamines

Release date: 2020-01-14 Views: 0

Source: Cypress Blue

Some valsartan and ranitidine drugs have problems with excessive levels of nitrosamines, which are class 2 carcinogens. The State Food and Drug Administration issued an opinion.

Nitrosamine Impurities Detected in Losartan and Ranitidine

Recently, the State Food and Drug Administration issued a public request for opinions on the "Technical Guiding Principles for the Study of Nitrosamine Impurities in Chemical Drugs (Draft for Solicitation of Comments)".

Opinions pointed out that, in order to standardize and guide the research and review of nitrosamine impurities in chemical drugs, the State Drug Administration has drafted the "Technical Guiding Principles for the Study of Nitrosamine Impurities in Chemical Drugs (Draft for Comment)". The public is soliciting opinions.

The "Draft for Comment" stated that since the detection of N-nitrosodimethylamine (NDMA) in Valsartan APIs in July 2018, various nitrites have been detected in other Sartan APIs. Amine impurities such as NDMA, N-nitrosodiethylamine (NDEA), etc.

Further investigation found that nitrosamine impurities were also detected in non-sartan drugs (such as ranitidine) from individual suppliers.

Nitramine impurities are substances of "cohort of concern" mentioned in the ICH M7 (R1) ("Assessing and controlling DNA-reactive (mutagenic) impurities in drugs to limit potential carcinogenic risk") guidelines; The list of carcinogens, NDMA and NDEA are both class 2A carcinogens.

According to the CPDB (Carcinogenicity Potency Database) database, there are already published carcinogenicity data for some nitrosamine impurities, such as NDMA, NDEA, N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N -Nitrosodibutylamine (NDBA), etc.

▍SFDA provides guidance for the control of nitrosamines

NDMA is a common nitrosamine found in water and food, including bacon and grilled meats, dairy products and vegetables. Everyone is exposed to a certain level of NDMA. The FDA and the international scientific community do not believe that ingesting low levels will cause harm. The acceptable intake limit for NDMA in the United States is 96ng.

Long-term exposure to higher-acceptable genotoxic substances such as NDMA may increase the risk of cancer, but people who take drugs containing equal or lower levels of NDMA per day for 70 years do not increase the risk of cancer.

At present, drug regulatory agencies in various countries are actively carrying out corresponding exploration and research on nitrosamine impurities in pharmaceuticals. This guiding principle will be continuously improved based on the research results of various parties and the principles of risk and benefit assessment.

The State Food and Drug Administration stated in its opinion that in order to ensure the safety and quality of the drug and controllable risks, the technical guidelines have been developed specifically for the registration of applications for marketing and the nitrosamine impurities in listed chemicals. Research and control provide guidance.

原因 Multiple causes of nitrosamine impurities

According to the current knowledge, there are various causes of nitrosamine impurities, such as process generation, degradation pathways and pollution introduction. Specifically, nitrosamines may be introduced through:

(1) Risk of introducing nitrosamine impurities from the process

It is currently known that NDMA and NDEA impurities may be formed through the nitrosation mechanism. That is, under certain conditions, amine compounds, especially secondary amines, react with sodium nitrite (NaNO2) or other nitrosating agents to produce nitrosamine impurities.

In the same process step, materials that can introduce secondary amines and nitrites (including starting materials, solvents, reagents, catalysts, intermediates, etc.) are used, and there is a high risk of introducing nitrosamine impurities; even in different In the process steps, materials that can introduce secondary amines and nitrites are used, and nitrosamine impurities may also be generated.

In addition to the secondary amine structure itself, the possible sources of secondary amines are: primary amines, tertiary amines, and quaternary ammonium may introduce secondary amine impurities; amide solvents (such as N, N-dimethylformamide, N-methyl Pyrrolidone, etc.) may produce secondary amines under appropriate conditions (such as: acidic, high temperature, etc.).

Possible sources of nitrosating reagents are: nitrite, nitrite, nitrite, substances prepared from nitrite (such as sodium azide, etc.), and oxidation of amine compounds.

When conditions are met, nitrosamines may also be produced during the production or storage of the formulation.

(2) Risks introduced by pollution

The use of raw materials (starting materials, intermediates, solvents, reagents, catalysts, etc.) contaminated with nitrosamine impurities during the production of APIs may bring the risk of nitrosamine impurities.

There is also a risk of introducing nitrosamine-based impurities when using recycled materials. Examples of contaminated recycled materials that have been found to be nitrosamines include o-xylene, tributyltin chloride (used as a source of tributyltin azide), and N, N-dimethylformamide (DMF).

Cross-contamination caused by incomplete cleaning of different varieties on the same production line.

(Three) the risk of degradation

Some drugs degrade itself to produce nitrosamines, such as ranitidine, which produces nitrosamines at high temperatures.

▍How to control nitrosamine impurities

(I) Basic Control Concept

Since the acceptable limit of nitrosamines in the human body is small, the detection and control of trace impurities is difficult. Therefore, the control of nitrosamines should be avoided and the control should be supplemented.

Avoidance mainly means that the production of nitrosamine impurities should be avoided according to the reasons for the production of nitrosamine impurities in the drug development stage from the choice of the process route of the drug substance, the selection and quality control of materials, and the optimization of process conditions , And strictly implement the operating specifications in the production process.

Drug manufacturers should fully communicate with the manufacturers of various materials (raw materials should include starting materials, solvents, reagents, catalysts, intermediates, etc., and preparations should include raw materials, excipients, packaging materials, etc.). Conduct a system assessment. The risk assessment method can adopt FMEA (Failure Mode Effects Analysis) or FMECA (Failure Mode, Effects and Criticality Analysis) described in ICH Q9 ("Quality Risk Management"), or other scientific and reasonable methods.

If the evaluation finds that there is a risk of nitrosamine-based impurities, first analyze the nitrite, and the necessity of using related reagents and solvents that may form nitrosamine-based impurities in the process, and try to avoid selecting nitrosamines as much as possible Production process of impurities.

The control-assisted strategy means that when the drug is assessed to have a risk of nitrosamine impurity residues and the related process cannot be avoided, this step should be adjusted to the early stage of the process as much as possible, and the subsequent multi-step operation is used to reduce the nitrosamine impurity residues. risk. At the same time, it is necessary to analyze the possible nitrosamine structure according to the process route, optimize the process, and develop a detailed process control strategy to ensure the effective removal of such impurities in the production process.

In the case of nitrosamine impurities generated by degradation, the conditions of degradation should be analyzed, and the risk of degradation impurities should be reduced by optimizing the production process, prescription, and storage conditions.

For varieties that are clearly at risk of residual nitrosamine impurities, a suitable analysis method should be established to ensure that the nitrosamine impurities in the finished product are below the limit requirements.

(Two) limit control

The control strategy for nitrosamine impurities in drugs is recommended to refer to the relevant provisions of the ICH M7 (R1) guidelines, and it should be ensured that the final control strategy and impurity limits have a sufficient and reasonable scientific basis. The carcinogenic risk of nitrosamine impurities is high, and the toxicological focus threshold (TTC) of 1.5 μg / day proposed by ICH M7 (R1) is not enough to fully control the risk.

The applicant shall determine the types of nitrosamine impurities that should be controlled according to the material attributes of the R & D variety, the technological route, the production process, the degradation situation, the analysis and test results, and the requirements of the regulatory agency.

The International Agency for Research on Cancer (IARC) lists nitrosamines as Class 2A carcinogens (may be carcinogenic to humans, but the evidence is limited and there is sufficient evidence for carcinogenicity in laboratory animals). ) Stipulates that it belongs to class Ⅰ mutagenic impurities. Therefore, the control of nitrosamine impurities in drugs should be based on compliance with ICH M7 (R1) requirements, so that the level of such impurities in drug substances and preparations is lower than Acceptable limit.

▍Fulfill risk control throughout the life cycle

The applicant should earnestly perform the main responsibility of drug quality management, carry out full life cycle management on the safety and quality of the drug, and avoid the introduction of nitrosamine impurities as much as possible. If it cannot be completely avoided, the nitrosate in the drug should be fully evaluated Risk of amine impurities and control nitrosamine impurities below safety limits.

For products declared for listing, the applicant should conduct a risk assessment of nitrosamine impurities during research and development, and fully study the varieties that have potential risks of nitrosamine impurities, and submit nitrosate in the corresponding section of the application information. Research data and test results of amine impurities. At the same time, the batches, batches of samples used for research must be representative and scientific basis.

For marketed drugs, the holder of the drug approval number / manufacturer should also actively evaluate the risks of nitrosamine impurities. If there is a potential risk of nitrosamine impurities, you can refer to this guideline and other relevant The guidelines require research to be carried out based on the results of the research to prevent or minimize exposure to nitrosamine impurities in patients.

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